**8. CD28-CD80/86 pathway**

#### **8.1 Abatacept**

Abatacept is a fusion protein of cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) with the Fc part of immunoglobulin G (IgG), selectively modulating CD80/ CD86:CD28 costimulatory signal, approved for patients with RA [85]. Its results have been evaluated in multiple RCTs in SLE. Abatacept failed to prove its efficacy in a phase 2 RCT of 118 patients with SLE with non-life-threatening manifestations, but with some encouraging results in some domains such as polyarthritis [86]. Abatacept has also been evaluated in patients with proliferative LN [87], failing to meet the primary endpoint of time to confirmed complete response but was associated with greater improvements of serological activity and 20–30% greater reduction of in mean urinary protein-to-creatinine ratio compared with placebo. In the phase 2 ACCESS trial [88], patients with LN received cyclophosphamide (Eurolupus) in monotherapy or in association with abatacept; no difference was observed in the primary endpoint of frequency of complete response at week 24 (33% in the placebo arm versus 31% in the abatacept group). Abatacept has also been assessed in a phase III trial in association with MMF [89], not reaching the primary endpoint of complete renal response at W52, but with a favorable effect in proteinuria and biomarkers.

#### **8.2 Lulizumab and theralizumab**

Lulizumab pegol is an anti-CD28 domain antagonist antibody, evaluated in a Phase 2 study in patients with active SLE, not reaching the primary endpoint of the proportion of responders using the British Isles Lupus Assessment Group (BILAG) based Composite Lupus Assessment (BICLA) at Week 24 [90]. Theralizumab, a CD28 superagonist [91], was evaluated in a phase II study; the trial was terminated for administrative reasons.

#### **8.3 CD40-CD40L**

CD40 ligand (CD40L) is expressed on naïve and activated CD4+ T cells and platelets [92]. Its receptor, CD40, is expressed on a wide range of cells including B cells. CD40L-CD40 interaction can contribute to autoreactive B cell survival [93], making it an attractive treatment target. In a phase 1 trial [94], dapirolizumab pegol, an anti-CD40L Fab' antibody fragment conjugated to polyethylene glycol (PEG), was safe and effective in patients with active SLE. Changes in the gene expression within the plasma cell and B-cell domains were also observed. These promising results were not confirmed in the phase 2 study [95] including patients with moderately to severely active SLE. BI 655064, another humanized anti-CD40 monoclonal antibody, was evaluated in patients with proliferative lupus nephritis in combination with mycophenolate mofetil [96]; the primary endpoint of complete renal response at W52 was not met. VAY736 and CFZ533, another 2 mAb blocking the CD40 pathway, are under investigation in patients with active SLE [97]. Finally, ruplizumab, another anti-CD40 ligand mAb, was evaluated in patients with LN leading to a decrease in hematuria, proteinuria, and biomarkers [98]; the trial was prematurely terminated due to thromboembolic complications.

#### **8.4 ICOS pathway**

Targeting inducible costimulator (ICOS) is a member of the CD28 superfamily, expressed on activated T cells and binding to B7RP1, present on B cells, dendritic cells, and monocytes [99], and playing a crucial role in humoral immunity, T-cell function, and differentiation to T follicular helper cells [100]. Two ICOSL antibodies (AMG557, MEDI-570) and one ICOSL and BAFF bispecific (AMG570) have been evaluated in phase 1 trials [101–104] with a good safety profile.
